Type-2 diabetes is increasing in prevalence at an alarming rate. The underlying cause of this disease is still not known. Patients with TTDM have insulin resistance and defective insulin secretion. It has been known for almost 30 years that insulin is secreted in high frequency intermittent pulses. However as these pulses result in only small oscillations in insulin concentration in the usual blood sampling sites, they have been hard to study. The laboratory of the PI in collaboration with Johannes Veldhuis at the University of Virginia have developed and validated methods that can now reliably quantify pulsatile insulin secretion in humans. Studies with these methods have revealed that almost all insulin is secreted in these intermittent pulses which occur at 6-minute intervals. We have also shown that the regulation of insulin secretion (for example after a meal) is achieved by the amplification of these pulses. Also, the liver is normally exposed to huge insulin concentration changes as these pulses are secreted into the portal vein that drains to the liver. No prior studies have examined the importance of these masses pulses on insulin action. In the present studies we plan to first establish how insulin secretion after meal ingestion is disturbed in patients with TTDM. We suspect that it will be deficient because the size of the insulin pulses is greatly decreased. Further, we suspect that this is because the number of cells that secrete insulin are decreased. We will test this by removing approximately 40 percent and 70 percent of these cells in a dog model with the expectation that we will create the same defect present in TTDM. We will also establish how important it is that the liver be exposed to these large insulin concentrations to function normally. This is important since patients with diabetes have to treat themselves with insulin in a very different manner. Designers of future systems to replace insulin in patients (e.g. by transplantation or devices) need to be appraised of the importance of pulsatile insulin secretion insulin action.